The Hyper-IgE Syndrome (HIES) is a primary immunodeficiency disorder characterized by eczema, elevated serum IgE, skeletal and connective tissue abnormalities, and diminished inflammatory responses. Patients are particularly susceptible to Staphylococcus aureus and Candida albicans, and suffer from skin abscesses, pneumonia with pneumatocele formation, and other deep-seated infections. HIES may present as a sporadic, autosomal dominant form (AD-HIES) that in a subset of patients results from heterozygous missense or in-frame deletions in the DNA-binding or SH2 domains of STAT3. It may also present as an autosomal recessive form (AR-HIES), which has some distinctive clinical features. STAT3 mutations in AD-HIES impair T helper (Th)17 cell differentiation, and our preliminary data reveal that Th17 differentiation is similarly impaired in HIES patients with normal STAT3. Accordingly, we hypothesize that HIES results from a heterogeneous group of genetic defects, including those affecting STAT3 itself and other targets along the STAT3 related pathways, that give rise to the overlapping but distinct phenotypes of AD- and AR-HIES. We propose to identify novel genetic defects giving rise to distinct subtypes of HIES not associated with STAT3 abnormalities by combination of functional immunological and cell signaling studies, forward genetics and candidate gene approaches. We also propose to employ a mouse model in which a HIES-associated STAT3 mutation has been introduced by Knockin mutagenesis to test the hypothesis that STAT3 mutations promote end organ damage by de-repression of tissue injury mechanisms, and that ineffective STAT3 signaling leads to aberrant differentiation of Th17 cells into regulatory T cells. These studies will identify novel genetic causes of HIES and illuminate pathogenic mechanisms common to different forms of the disease. PUBLIC HEALTH RELEVANCE: The hyper IgE syndrome (HIES) is a primary immunodeficiency disorder characterized by eczema, elevated serum IgE, recurrent infections, skeletal and connective tissue abnormalities, and diminished inflammatory responses. It exists in different forms, one of which has been found to result from mutations in the transcription factor STAT3. We are proposing to identify novel genetic defects that would contribute to other forms of HIES that have normal STAT3. Our studies would uncover novel mechanisms by which genetic factors contribute to inflammation and immunodeficiency, and will help identify novel therapeutic approaches relevant to both this disorder and more common allergic inflammatory diseases such as atopic dermatitis.